Researchers have discovered key details of how stroke or traumatic brain injury can trigger Alzheimers disease (AD) by enhancing formation of brain-clogging amyloid plaques. Their experiments established that executioner enzymes that kill brain cells during stroke or head trauma also interfere with the normal disposal of an enzyme that helps generate plaque. This interference increases the level of the enzyme in brain cells, they found.
The researchers, led by Giuseppina Tesco and Rudolph Tanzi of Massachusetts General Hospital, reported their findings in the June 7, 2007, issue of the journal Neuron, published by Cell Press.
The researchers sought to understand the mechanism by which stroke or brain injury causes the increase of an enzyme called BACE in the brain. BACE is a protein-cleaving enzyme that snips apart a brain protein called amyloid precursor protein to form a shorter protein called A beta peptide. It is this A beta peptide that is the building block for the amyloid plaques that are a hallmark of AD.
The researchers discovered that particular enzymes produced during brain injury, called caspases, somehow also enable BACE to linger in brain cells. Caspases are so-called executioner enzymes that destroy brain cells such as those damaged by oxygen deprivation during stroke.
In further exploring the link between caspase activation and higher BACE levels, the researchers found that one of the proteins snipped apart by caspase activity is GGA3. This protein is an adaptor protein necessary for shepherding BACE to the cells garbage disposal machinery, the lysosome. The researchers found that caspase snipping of GGA3 not only eliminates GGA3's ability to tag BACE for destruction but that the resulting fragments of GGA3 actively interfere with BACE disposal.
To test the role of GGA3, the researchers silenced activity of the GGA3 gene in brain cells, finding that the silencing caused increased levels of BACE an
Contact: Erin Doonan